The production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, starting from meso-2,3-bis(benzylamino)succinic acid in the form of its dialkali metal salt, is known in the art. For example, Seiter, U.S. Pat. No. 5,151,525 ("Seiter '525") discloses a process in which phosgene is used as the reagent, in an alkaline-aqueous/organic two-phase solvent system, that causes the linkage of the two secondary nitrogen atoms via a carbonyl group resulting in ring formation. The reaction disclosed in Seiter '525 employs anisole as the essentially water-immiscible solvent.
The phosgene reagent of Seiter '525, however, is highly toxic and potentially explosive under the influence of other gases or certain reaction liquids. Thus, its use is extremely dangerous when carelessly handled, or supervised, and special precautions are required in its transport, storage and use, e.g., the use of safety devices is essential in any apparatus that comes into contact with phosgene.
A process for the production of the aforementioned cyclo acid that also starts from meso-2,3-bis(benzylamino)succinic acid in the form of its dialkali metal salt, but using an alkyl, haloalkyl or aryl chloroformate in place of phosgene for the ring formation, is disclosed in Japanese Patent Publication (Kokai) No. 8270/1976 ("JP 8270/1976"). Although the disclosed process avoids the disadvantages of phosgene outlined above, it still has other equally serious disadvantages, which may explain why the use of chloroformates has hitherto not been adopted. Apart from the high costs involved, some other disadvantages of using chloroformate are, for example, the production of diphenyl carbonate and phenol as unavoidable byproducts. The diphenyl carbonate separates as a viscous mass from the aqueous reaction solution and clogs up the reactor components and the pH probe. For this reason, pH values cannot be reported accurately, which is of critical significance for the controlled performance of the reaction. However, the cyclo acid can only be produced in the desired yield by using phenyl chloroformate, which is the preferred reagent according to the examples disclosed in JP 8270/1976.
The first reaction step of the process disclosed in JP 8270/1976 involves the reaction of phenyl chloroformate with meso-2,3-bis(benzylamino)succinic acid dialkali metal salt, along with the cleavage by hydrochloric acid, forming a monourethane intermediate, which then reacts further to form the cyclo acid. The resulting alkali phenolate reacts with phenyl chloroformate to form the byproduct diphenyl carbonate. The remaining hydrochloric acid can be neutralized by the addition of alkali metal hydroxide solution, whereby the pH value should be neither too low nor too high. If the pH is too low, the meso-2,3-bis(benzylamino)succinic acid precipitates out and cannot be reacted. Moreover, the meso-2,3-bis(benzylamino)succinic acid combines with separated diphenyl carbonate to form a viscous mass, leading to further clogging of the reactor components, including the stirrer. If the pH is too high, the phenyl chloroformate hydrolyzes too rapidly, leading to unnecessary consumption.
Furthermore, the precipitation of the cyclo acid by the addition of a strong acid is difficult to accomplish, since this often separates as a viscous mass, as disclosed in JP 8270/1976, and can result in a further clogging of the reactor components, including the stirrer.